Roche’s fenebrutinib on par with Ocrevus for multiple sclerosis

Edited by Robert McTiernan··3 min read

Switzerland-based Roche announced positive late-breaking Phase III results from the FENtrepid study evaluating fenebrutinib in patients with primary progressive multiple sclerosis (PPMS). Fenebrutinib is an investigational, oral Bruton’s tyrosine kinase (BTK) inhibitor designed to be brain-penetrant, allowing it to target both B cells and microglia to address the chronic inflammation thought to drive long-term disability. The announcement marks a significant milestone as fenebrutinib is the first investigational therapy in over a decade to meet its primary endpoint of reducing disability progression in a PPMS population compared to an active comparator.

Trial specifics

The Phase III FENtrepid study (NCT04544449) is a multicenter, randomized, double-blind, double-dummy trial involving 985 adult patients with PPMS. Participants were randomized to receive either twice-daily oral fenebrutinib or the current standard of care, Ocrevus (ocrelizumab), administered via intravenous infusion every six months. The trial met its primary endpoint of non-inferiority to Ocrevus in reducing the risk of 12-week composite confirmed disability progression (cCDP12), which utilizes a combination of the Expanded Disability Status Scale (EDSS), the timed 25-foot walk (T25FW), and the nine-hole peg test (9HPT).

Data presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026 showed that fenebrutinib numerically reduced the risk of disability progression by 12% compared to Ocrevus (HR 0.88; 95% CI: 0.75, 1.03), with treatment curves separating as early as 24 weeks. A key efficacy outcome was the 26% reduction in the risk of worsening on the 9HPT, indicating a strong treatment effect on upper limb function (HR 0.74; 95% CI: 0.56, 0.98). A post-hoc analysis focused specifically on the composite of EDSS and 9HPT suggested a 22% risk reduction.

The AllSci BriefSystematic R&D and deal news. Daily.

The safety profile of fenebrutinib was comparable to Ocrevus. Common adverse events (≥10%) included infections (67.0% vs 70.9%), nausea (12.0% vs 7.1%), and hemorrhage (10.2% vs 8.1%). While transient and reversible liver enzyme elevations were more frequent in the fenebrutinib arm (13.3% vs 2.9%), no cases of severe liver injury (Hy’s law) were observed, and all cases resolved after drug discontinuation. Serious adverse events occurred in 19.1% of patients receiving fenebrutinib. Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer, described the results as a “potential scientific breakthrough” for a community with only one approved treatment option. Roche plans to submit a complete data package to global regulatory authorities following the readout of the Phase III FENhance 1 study in relapsing MS (RMS), expected in the first half of 2026.

Research context

Fenebrutinib belongs to the BTK inhibitor class, which represents a novel approach to MS by modulating B cells and microglia within the central nervous system. This is biologically relevant to PPMS, where neurodegeneration often proceeds independently of the acute peripheral inflammation seen in relapsing forms. By crossing the blood-brain barrier, fenebrutinib aims to target the chronic smoldering inflammation associated with progressive disability. Currently, the asset remains unapproved globally for any indication. PPMS represents a high unmet need, as Ocrevus is the only existing US FDA-approved disease-modifying therapy for this patient population.

The competitive landscape for PPMS and RMS treatments includes several late-stage BTK inhibitors and high-potency monoclonal antibodies:

  • Roche’s Ocrevus (ocrelizumab), a CD20-targeted antibody that currently serves as the only approved therapy for PPMS and the active comparator in the FENtrepid trial.
  • Sanofi’s tolebrutinib, an oral BTK inhibitor that recently showed mixed results, failing in relapsing MS but showing benefit in non-relapsing secondary progressive MS (nrSPMS) in the Phase III HERCULES trial.
  • Merck KGaA’s evobrutinib, which failed to meet primary endpoints in Phase III RMS trials in late 2023, highlighting the high failure rate within the BTK inhibitor class for MS.
  • Novartis’ remibrutinib, which is undergoing evaluation in Phase III trials (REMEDY 1 and 2) for relapsing forms of MS, with a focus on establishing a superior safety profile regarding liver enzyme elevations.